Engineering Necroptosis-Induced Vesicular Nanocarriers for Homologous Targeted Melanoma Therapy

Melanoma is a highly aggressive malignancy with limited therapeutic options, highlighting the need for efficient tumor-targeted drug delivery strategies based on nanomaterials. Herein, we report a necroptosis-induced biogeneration strategy for constructing tumor-derived biomimetic nanocarriers for homologous targeting in melanoma therapy. Shikonin-loaded amorphous calcium carbonate nanoparticles (SKN@Ca NPs) were synthesized and used as nanoinducers to trigger necroptosis in melanoma cells. During this process, cells released membrane-derived vesicles termed necroptotic bodies that simultaneously encapsulated internalized SKN@Ca NPs, resulting in the in situ formation of necroptosis-induced nanocarriers (SKN-Ca@NIN). The obtained SKN-Ca@NIN retained membrane proteins from parental tumor cells and therefore exhibited biomimetic vesicular structures and homologous targeting capability toward melanoma cells. In vitro studies demonstrated that SKN-Ca@NIN showed favorable biosafety toward normal cells while effectively inhibiting melanoma cell proliferation. Mechanistically, intracellular degradation of the calcium carbonate core triggered Ca 2+ release, while shikonin promoted reactive oxygen species (ROS) accumulation, leading to severe ionic and oxidative stress that disrupted tumor cell homeostasis. This work provides an in situ necroptosis-induced nanocarrier platform for efficient tumor accumulation and therapy via a homologous targeting strategy.